HIV-infected patients and SIV-infected macaques on highly active antiretroviral therapy (HAART) present with residual immune activation (IA) and inflammation (INFL), which are indicators of poor prognosis even in the setting of controlled viral replication. The causes of IA/INFL under antiretroviral therapy (ART) are not yet fully elucidated. It is currently not known whether IA/INFL is determined by residual virus replication below the detection limits of conventional assays or by irreversible damage of the gut that allows leakage, independent of virus replication. Also, it is not known which tissues/s and what immune cell type/s are predominantly responsible for the residual IA/INFL in the treated patients. It is not clear whether or not the immunologic status of the patient at the time of ART initiation impacts the residual IA/INFL. The consequences of increased IA/INFL in the presence and absence of ART are not completely understood. For example, although observational studies in humans and nonhuman primates (NHPs) suggest a link between IA/INFL and increased cardiovascular (CV) risk, direct proof of causal link is lacking. We will address these aspects of HIV pathogenesis and management of HIV-infected patient in this competitive renewal of RO1 AI064066, which is our grant to study SIV pathogenesis in NHPs. During the previous funding period, which generated 43 scientific publications, we developed the SIVagm- infected pigtailed macaque (PTM) as an ideal model to study the microbial translocation (MT)-induced IA/INFL and SIV-related CV comorbidities. We also identified a combination of drugs that significantly reduces MT and IA/INFL in the highly pathogenic SIVagm infection in PTMs. As a result of this intervention, the coagulation markers are reduced in this model. Based on these preliminary data, our hypothesis is that MT induces generalized IA/INFL that increases the CV risk in HIV-infected patients, including those that control virus replication under HAART. To test this hypothesis in our clinically relevant system, we will use interventions to reduce MT in the absence or in the presence of ART and determine the consequences of these interventions on IA/INFL and CV risk. Treatments will be initiated at key time points during acute, chronic and terminal SIV infection, to model relevant clinical settings and assess efficacy in patients with different immune status. Invasive sampling will be performed to measure virus replication, IA/INFL and to diagnose CV lesions. Such experiments cannot be performed in humans. This study design will allow us to determine: (i) the relative role of virus replication and MT in inducing IA/INFL and CV disease during each stage of infection, in the presence or in the absence of ART; (ii) the origin of IA/INFL under ART; (iii) the timing and the pathways of CV disease development during SIV infection; (iv) if reduction of MT will normalize IA/INFL and CV risk under ART; (v) the role of immune status in the response to these two therapeutic approaches; (vi) the optimal timing for initiating individual and combined therapies. These highly translational experiments address major gaps in our current knowledge of HIV pathogenesis and treatment and have the potential to improve clinical management and survival of HIV-infected patients by targeting residual IA/INFL under ART, immune recovery and HIV/SIV-related CV disease.